When Paul Bert, a French physiologist, started to stitch mice together in 1864 he probably wasn’t thinking about the fountain of youth. His main interest was in animal grafting; the way tissue transplants could survive away from the body and affect a biological system (1).
Bert’s successful attempts in parabiosis, the surgical joining of two entire living animals, should establish whether tissue grafts from one animal could also be used on the joined animal and what the immunological implications were. Besides, this experiment also proved that blood from one mouse circulated freely into the other mouse and an “extended physiological and pathological connection result[ed] from the vascular connection”.
About 150 years later, these experiments are once again picked up by scientists. But this time they inspire a whole new scientific discipline: the understanding of aging.
Professor Amy Wagers learned the technique of creating parabiotic mice during her time as a post-doc in Irving Weissman’s lab in Stanford. Her work and that of Stanford colleagues, working in Thomas Rando’s lab at the time, indicated intriguing effects that parabiotic mice could have on each other.
When old mice (19-26 months) were joined with young mice (2-3 months), sustained muscle injuries healed much faster than in old mice alone. While it is reasonable to believe this could have been due to the migration of “young” muscle stem cells from the shared circulation into tissues of old mice, Conboy et al. could show that another mechanism was at work.
The improved regeneration in old mice was in fact due to increased activation of so-called satellite cells within their muscle tissue. These cells are progenitor cells found in mature muscle which can give rise to other satellite cells or more differentiated cells. Local progenitor cells from old mice obviously still had the ability to divide and regenerate the tissue, but “old” blood alone could not stimulate them sufficiently enough to do this. They needed the rejuvenating influence from young blood to kick-start their molecular pathways back into youthful capacity.
Influence to scientists usually means factors. Is there a combination of factors – proteins, molecules, hormones…? – in a young mouse’s blood that could be used as a power cocktail for old mice and heal them from diseases? And, more importantly, will it work in humans?
Water from the fountain of youth is currently being analysed – and publications are piling up at a rapid pace with several highly interesting findings just last year.
Following the initial report in 2004, many factors in young blood have been identified that can, also in vitro, boost the regenerative capacity of aged tissue and reverse symptoms of aging. An influence of Wnt and TGFβ pathways has been confirmed in muscle aging and regeneration. Cytokines and chemokines have been found to have an impact on neurogenesis and aging brain function. Oxytocin, a hormone well known for its role in lactation and social behaviours (also frequently hyped as “love hormone”), has been suggested to play a role in age-dependent muscle degradation. And most recently another factor, GDF11, initially reported to improve performance and size of failing hearts, was found to recover cerebral vasculature and enhance neurogenesis as well, all aspects that are highly affected by age-dependent deterioration.
Considering this wealth of findings within just a few years, humankind certainly owes the parabiotic mice a few favours (and by that I don’t mean the alleviation of their old age-symptoms). Older reports from the 1970s also hint at a longer lifespan achieved by old mice that were attached to young mice. However, a concluding remark on this is still outstanding.
But how is this astonishing effect even possible? To answer this, it helps to understand why humans age.
From the molecular perspective aging is a progressive decline in a cell’s ability to maintain homeostasis and regenerate. It is a process that uniformly affects all cells in the body – and as whole tissues begin to degrade organs lose their efficiency, deteriorate or are afflicted by diseases; with all the known physical, psychological and social consequences for the respective person.
Some organs or cell types might keep their regenerative capacity longer than others, but they all eventually age and degrade. As the smallest contributors within the organism lose their integrity, the entire human being is destined to suffer the consequences.
The current view is that aging is caused by degenerative changes in tissue stem cells, their niches and systemic factors that regulate stem cell activity. As stem cells age, many processes can influence or undermine their function. Because stem cells persist for life and give rise to all other cells in the human body, degeneration can have dire consequences. To function properly they need to adhere to an exact balance between active and inactive (senescent) phases, and whatever DNA damage they accumulate during their long life-span will be passed on to all daughter generations.
Indeed, stem cells in tissues have been found to acquire many changes with age. They might
- respond differently or not at all to tissue injury,
- proliferate less/ might not divide as they should or produce the “wrong kind” of daughter cells,
- be unable to keep up with their regular cellular functions,
- die (apoptosis) or stay permanently in an inactive state.
Changes that affect stem cell function can be caused by the accumulation of toxic metabolites in cells. Reactive oxygen species (ROS) build up (one theory for this is that mitochondria integrity regresses over time which increases ROS production) and can profoundly change a cell’s function and fate control. DNA damage is accumulated over time within the cell’s genome. Telomeres, which should protect the chromosomes and prevent DNA loss, are becoming shorter. However, the real extent of DNA damage in an aging cell is difficult to judge. Some genomic alterations might just represent age-related strategies to deal with a changed physiological situation. There are many repair mechanisms that can potentially fix DNA damage. However, studies have shown that the efficiency of these mechanisms declines with age. Interestingly, naturally occurring mutations in important repair pathways can result in diseases which mimic the process of aging (progeroid syndromes).
So if aging just represents an overall exhaustion of the cells and their capabilities – is there anything we can do about it?
Fact is that for many of the “symptoms” of aging there are – at least theoretical – approaches that could improve or even fix each issue on a molecular basis. DNA damage repair pathways can be activated, protein degradation prevented, mitochondrial function restored and to replenish the pool of healthy stem cells, transplantations might be possible in the near future (e.g. haematopoietic stem cells have been routinely transplanted in the clinic for decades). Find a more in-depth review about this here.
But are there strategies that would tackle these problems all at once and in a controlled manner to maintain a healthy balance? All of the above mentioned factors have one thing in common: they are pushing the aged stem cell back into a more active, youthful state. Activation of stem cells indeed seems to be the most common mechanism in rejuvenation of old mice after parabiosis.
The factor I mentioned earlier, GDF11, can trigger all sorts of miraculous changes, from reducing cardiac hypertrophy to enhancing neural stem cell function with as far reaching consequences as improved physical and mental activity. It’s quite fascinating to see how much youthfulness can be restored this way.
But accumulated DNA damage might still remain and limit the extent to which a cell can be rejuvenated. There is also the question whether stem cells have an epigenetic memory for aging.
Stem cells accumulate epigenetic changes during their life-time in response to external stimuli (e.g. stressful situations), and studies have shown that these changes can even be passed on to offspring. Some epigenetic variations have been linked specifically to aging. The cell might downregulate certain enzyme levels as it adjusts to a different metabolism and so on.
However, these epigenetic changes can be reversed. Pharmacological modulation already allows the altering of histone modifications and could therefore be able to erase some of the memory. A more extreme approach is used in induced pluripotent stem cells (IPSCs – look here for more details) where the entire previous “memory” of a cell is erased and the cell reverts back to a “blank canvas” pluripotent state. Given there’s not too much hardware damage in a cell’s DNA and all the necessary instructions for the building blocks are intact, it should be possible to repair everything else and reset to status quo. Would that make a cell immortal? Could we just keep erasing the age-memory and rejuvenate them every few years? How long would a cell like this last? Would we even want to amend cell functions that we have gained (or lost) over the years and are all changes that come with age necessarily bad?
Even though it is technically possible to reprogram cells in a dish, the approach might not be feasible for an entire organism. Prof Wagers’ rejuvenating factor is certainly a step closer to home and together with Prof Lee Rubin she is currently working on getting it into human clinical trials.
Another trial with human blood plasma, donated by people under the age of 30 to patients with mild to moderate Alzheimer’s disease, has already been initiated by a different research group and results are awaited eagerly.
Professor Wagers clarifies that her experiments are not aimed at “de-aging” animals. They are just designed to restore function to tissues and repair damage.
Whether this can be reliably sustained over a long period is unknown. To push aging stem cells beyond their limits might damage them additionally with drastic consequences later on. Besides, the oldest and best-known associate of the fountain of youth is also still looming. The only kind of cell that has actually achieved true immortality and boundless replicative power: cancer. Anyone attempting to force cells into improved regeneration and growth will undoubtedly have to consider the possibility of tumour development.
Prof Wagers will give a talk at the KCL Centre for Stem Cells & Regenerative Medicine in April. More details can be found here in due time.
Reference 1: A History of Organ Transplantation: Ancient Legends to Modern Practice. David Hamilton.